Method for the relief of cough with a thebaine derivative



United States Patent 3 506,765 METHOD FOR THE RELIEF OF COUGH WITH A THEBAINE DERIVATIVE Isao Seki, Hiromu Takagi, Shinsaku Kobayashi, Issei Iwai, and Haruhiko Minakami, Tokyo, Japan, assignors to Sankyo Company Limited, Tokyo, Japan No Drawing. Filed Feb. 26, 1968, Ser. No. 707,952 Int. Cl. A61k 27/00 US. Cl. 424-260 9 Claims ABSTRACT OF THE DISCLOSURE New use of 14-hydroxy-dihydro-6B-thebainol 4- methyl ether as an antitussive. Such thebainol exerts a higher antitussive activity on coughs due to a wide variety of respiratory diseases in a human subject and far less side effects, as compared with prior antitussive drugs, especially codeine phosphate, in an amount, calculated on a daily dosage basis, ranging from 3 to 12 mg, preferably 6 mg, usually three times a day at a single dose of 1-4 mg., preferably 2 mg., usually in the form of pharmaceutical composition such as tablets, solutions for injection and the like.

This invention relates to a new use of thebaine derivative as a medicine. More particularly, this invention relates to a new use of 14-hydroxy-dihydro-6 3-thebainol 4-methyl ether as an antitussive.

A considerable number of chemical substances have been used as an antitussive for the relief of various types and severities of coughs which are frequently and voluntarily produced in various respiratory diseases including pulmonary tuberculosis, acute or chronic bronchitis, pneumonia, bronchial asthma, gangrene of the lung, cancer of the lung etc. Unfortunately, most of these substances have not achieved full success in the relief of cough, since some of them exhibited a high antitussive activity only in extremely limited clinical applications; even if they showed a good antitussive activity in general clinical applications, they were of short duration or exhibited undesired side effects; their physiological compatibilities were not so good as they could be liberally employed for the treatment of coughs due to a wide variety of respiratory diseases; their effective doses could approach near the order of their toxic doses; and so on.

As a typical one, codeine, one of opium alkaloids, is widely employed, usually in the form of the phosphate thereof, as an antitussive for the relief of cough. However, as being common to narcotic drugs, such an alkaloid shows some undesired side effects; for example, central excitation and depression, constipation, nausea and emesis, blood pressure depression, tolerance and addiction etc. and, thus, careful consideration is required in order to gain a safe and satisfactory antitussive effect.

Accordingly, there is the need for a new class of antitussive which will exert a higher antitussive activity and less undesired side effects.

Now, it has been, unexpectedly, found that the 14- hydroxy-dihydro-6,8-thebainol 4-methyl ether exhibits in a human subject at a daily dosage of 3-12 mg. a higher antitussive activity against cough due to a wide variety of respiratory diseases, as compared with prior antitussive drugs, and alsoit will be more significant-that said thebainol has little or far less side effects in clinical applications, particularly no vomiting action as well as much Patented Apr. 14, 1970 weaker additive, constipating and respiratory and blood pressure depressant actions, as compared with wellknown antitussive drugs, for example, codeine phosphate.

It is, therefore, a principal object of this invention to provide a novel process for the relief of cough which comprises administering to a human subject suffering from cough a specific antitussive amount of 14-hydroxy-dihydro-6B-thebainol 4-methyl ether.

It is also contemplated within this invention to provide a medicament for the relief of cough which contains as an active ingredient antitussive amount of the aforesaid thebainol.

Other objects and advantages of this invention will be apparent to those skilled in the art from the detailed description which follows.

The 14-hydroxy-dihydro-6/3-thebainol 4-methyl ether which may be effectively employed in this invention is a known substance represented by the formula and it may be readily obtained by several known procedures, for example, by reacting l4-hydroxy-dihydro-thebainone 4-methyl ether with metallic sodium and a secondary alcohol (Japanses Patent No. 445,922).

The process of this invention for the treatment of a human subject suffering from cough may be conveniently carried out by oral administration, but parenteral administration may also be employed, particularly for emergency treatment.

The antitussive amount to be administered for the relief of cough, that is, the dosage of the active compound in the process of this invention should be determined taking careful consideration of the ages and weights of the patient, frequencies and severities of coughing, possible side effects on a human body and other factors to be studied on determining the dosage of narcotic drugs. In the process of this invention, the average total daily dosage for adults of said thebainol may be advantageously within the range of 3-12 mg., preferably 6 mg., while larger daily dosages may be employed only for emergency treatment. The above-specified daily dosage of said thebainol may be preferably given in multiple divided doses, suitably three times a day at a single dose of 1-4 mg, preferably 2 mg. The dosage for infants and children generally depends on ages and weights of the patient, and is generally smaller than that of adult as defined hereinabove.

The active thebainol may be administered alone or in the form of pharmaceutical compositions but it is preferred to administer said thebainol in the form of pharmaceutical compositions.

In this invention, the antitussive pharmaceutical composition comprising l4-hydroxy dihydro-6/3 thebainol 4-rnethyl ether as active ingredient and a compatible pharmaceutical carrier can be provided. The compositions can be in the form of parenteral composition including solutions suitable for injection, or the compositions can be in the form of oral compositions including tablets, As stated above, the said l4-hydroxy-dihydro-6fi-thecapsules, powders or oral suspensions and syrups. The bainol 4-methyl ether exhibits a higher antitussive activity compatible pharmaceutical carrier can be either solid or and less side effects, as compared with prior antitussive liquid material. The carrier should be essentially nonagents, for example, codeine phosphate. toxic. 5 Such beneficial pharmacological properties of said the- The composition of this invention can be in the form bainol will be discussed hereinbelow in greater detail, of parenteral composition, preferably, in the form of With reference to those. data available from a series of solutions suitable for injection which comprises l4-hylaboratory experiments and clinical trials. droxy-dihydro-6{3-thebainol 4-methyl ether as active in- I. LABORATORY EXPERIMENTS gredlent in a suitable, compatible and non-toxic solvent. 10

The preparation of a sterile solution suitable for in- Ahtitussive activity measured y a mechanically jection can be accomplished by any conventional method, Stimulating method With guinea p trachea for example, by admixing the active ingredient with water or isotonic saline and sterilizing the resulting solu- Method: Followlhg e method reported y f g tion, f example, by filt ti or b heating h Concenet al. in Yakugaku Zassht [Journal of the Pharmaceutical tration of said thebainol in such a solution may be usu- Soelety of Japan, 78, 553 the eXPenmeIlt Was ally varied within the range of about 5-40 w./v. percent, Carried out by employing male guinea P With y i.e. about 0.5-4 mg. of the thebainol per ml. of a fin- Weights of 250-400 gat 30 and 60 minutes after ished solution. In those solutions suitable for injection, Subcutaneous administration of the test Compounds there may be such adjuvants as a preservative or an antiy yy l -t y and Codeine bacterial agent. phosphate), mechanical stimuli were given, and when no As another form of the pharmaceutical composition in gh Oeellrred t0 tWO more t the t 1 this invention, the active ingredient can be used in the p und W s r garded as effective. Then, ED was calcuform of a tablet. The tablet is comprised of usually the lated by the up-and-down method. active ingredient and the carrier which includes a suit- Results:

able pharmaceutical vehicle, binder or filler, such as ED mg./kg. starch, gelatin, lactose, talc, cellulosic material, stearic 14-hydroxy-dihydro-6,8-thebainol 4-methyl ether 0.44 acid, magnesium stearate and the like. Any of the other Codeine phosphate 11.00

tableting materials generally used in pharmaceutical practice may be employed, unless they are incompatible with It Will be Seen from the above results that y ythe active ingredient. In one of the preferable procedures dihydm"6B-thebaih0l 4-Ihethy1 ether eXhihitS 25 times as for making a tablet in this invention, the prescribed inhigh in an antitussive activity as codeine phosphate. gredients are compressed bya conventional means into (2) Acute toxicity in mice tablets, each usually containing the active 1ngred1ent at about 0.5 to 4 mg. dosages. The tablets can be coated, if Method: Followlng a convehtlohal Procedtlre desired, with any of the conventional tablet coating mamohly p y in the art, the experiment Was Carried terials. out by employing several groups of male mice with body In another pharmaceutical composition in this invenweights of 17-22 and intravenously, Orally or tion, the active ingredient can be filled into an ordinary eutaneously administering the test Compounds yhard or soft gelatin capsule. The capsule may also condr0Xy-dihydr0-6fl-thehainol 4-Inethy1 ether and Codeine tain a solid or non-solid, compatible, non-toxic material. p p t0 the host animals- Then, so was Calcu- The preferred capsule ingredients include solid filler, lated by the Litchfield-Wilcoxon method. such as starch, lactose, talc, stearic acid, magnesium Results: The results are given hereinbelow.

Route LDsu g/ Intravenous Subcutaneous Oral +The values in each parenthesis mean the 95% confidence limit.

stearate and the like. Generally, in each capsule, the ac- It Will be seen from the above results that, in the case tive ingredient is added in an amount of from 0.5 to of intravenous administration, 14-hydroxy-dihydro-6fl- 4 mg. thebainol 4-methyl ether exhibits the almost same order In another pharmaceutical composition in this inven- 5a of acute toxicity as codeine phosphate, While, in the case tion, the active ingredient can be in the form of p wder, of oral and subcutaneous administration, the former exsyrup or suspension. Usually, from about 0.1 to 0.5% by hibits about /2% time as low acute toxicity as the latter. weight of the active ingredient may be included in this composition. The preparation of these forms of the phar- II. CLINICAL TRIALS maceutical composition may be accomplished by any of the conventional methods. In particular, it is preferred in Trial A the form of powder that the powder containing the active ingredient in the given concentration is previously (1) Patlehtt 42 (311160815 0T Pt11mh3tyt11befeu10$1$)- prepared i a large amount and such powder may be (2) Dose levels, Ifrocedures and Results: A double-blind ministered in the desired amount or the powder cross-over design with randomlzed sequence of treatments taining the active ingredient in higher concentration are was aflcfpted using a certain number of P and tablets previously prepared and, before usage, such powder may cohtalhlhg as an active ingredient y yy flbe diluted with a suitable pharmaceutical carrier to make thebainol 4'Ihethy1 etheh Daily dosage of the active rh prescribed d gredient Was 6 mg. per day with 3 divided dose unit The pharmaceutical carrier used for the preparation forms- The Patients Were administered With the Placebo of syrup or suspension may be any of those employed for 5 days and, consecutively, with the tablet for further by the conventional pharmaceutical practice. 5 days. Such dosing schedule was repeated for 29-80 Coloring agents, aromatics and other adjuvants may days. he further admixed with the present composition, if de- During the period of trial, the frequency of coughing sired. Was observed seven times (i.e. before and after adminis- -thebainol Side efieet hydro-6/EZ-thebainol 4-methyl ether in each ampoule (1 ml.).

(2) Capsule: 1 mg. of 14-hydroXy-dihydro-6fi 4-methyl ether in each capsule (300 mg).

r Results:

0 (1) Solution for injection: The antitussive activity of 14-hydroxy-dihydro-65-thebainol 4 -methyl ether was evaluated on 28 patients suffering from a wide variety of respiratory diseases with various types and severities of Trial B 10 coughing. The antitussive effect on pulmonary tuberculosis is shown in the following Table I, and that on other respiratory diseases in the following Table II.

TABLE I.ANTITUSSIVE EFFECT ON PULMONARY TUBERCULOSIS (WITH SOLUTION FOR INJECTION) Sex, Type of Dose, Name Age Disease cough mg. Antitussive effect tration, and after going to bed) every day and scored as point 0, l, 2 or 3 according to a scale consisting of 4 grades, which have been previously defined by those skilled in the art, based upon the frequencies of coughing.

After expiration of the trial period, the summing up and statistical analysis of scored results show that the antitussive activity of 14-hydroxy-dihydro-6B-thebainol 4-rnethyl ether differs to a statistically significant degree at 0.05 level from that of the placebo.

Preparation:

( 1) Solution for injection: 2 mg. of 14-hydroxy-di- TABLE II.-Comtinued Side efieet Type of Dose, cough mg. Antitusslve effect Sex, Case Name Age Disease 2 111999998544 fl6fl666555556255 N0'rE.In the Tables I and II, the symbols and in the Antitussive effect column mean clinically excellent and good antitussive efiects, respectively; the symbol in the Side effect column being not observed.

(2) Capsule.-The antitussive activity of 14-hydr0xydihydro-6fi-thebainol 4-rnethyl ether was evaluated on The antitussive effect on pulmonary tuberculosis is shown in the following Table III, and that on other respiratory 58 patients suffering from a wide variety of respiratory 2O diseases in the following Table IV. diseases with various types and severities of coughing.

TABLE III.ANTITUSSIVE EFFECT ON PULMONARY TUBERCULOSIS (WITH ORAL ADMINISTRATION OF CAPSULES) Antitussive effect Duration Type of Dose, Frequency of (Days or cough mg. administering Times) Name Sex, age Disease Case:

Pulmonary tuberculosis See footnote bottom of Table IV.

TABLE IV.ANTITUSSIVE EFFECT ON OTHER RESPIRATORY DISEASES (WITH ORAL ADMINISTRATION OF CAPSULES) Duration Anti- (Days or Type of Dose, Frequency of tussive cough mg. administering Times) effect Sex, Name Age Disease Case:

NOTE In these Tables III and IV, the symbols and in the Antitusslve efiect column mean clinically excellent, good and poor antitussive efieets, respectively.

EXAMPLE 1 Solution for injection 14-hydroxy-dihydro-6/3-thebainol 4-methyl ether--2 mg. Sodium hydroxideq.s. to pH 7.0 Distilled water for injectionq.s. 1 ml.

The active ingredient was dissolved in part of the water, the pH of the solution was adjusted to pH 7.0 with the sodium hydroxide and then the volume was brought up to 1 ml. The solution was filtered, filled in a conventional ampoule and autoclaved.

EXAMPLE 2 Soultion for injection 14-hydroxy-dihydro-6/3-thebainol 4-methyl ether-2 mg. Benzyl alcohl10 mg.

Sodium chloride5 .8 mg.

Hydrochloric acid-q.s. to pH 7.0

Distilled water for injectionq.s. 1 ml.

The active ingredient, the alcohol and the chloride were dissolved in part of the water, the pH of the solution was adjusted to pH 7.0 with the hydrochloric acid, and then the volume was brought up to 1 ml. The solution was filtered, filled in a conventional ampoule, and autoclaved.

EXAMPLE 3 Solution for injection 14-hydroxy-dihydro-613-thebainol 4-methyl ether1 mg. Benzyl alcoholmg.

Sodium chloride-59 mg.

Distilled water for injectionq..s. 1 ml.

The active ingredient, the alcohol and the chloride were dissolved in part of the water and then the volume was brought up to 1 ml. The solution was filtered, filled in a conventional ampoule, and autoclaved.

EXAMPLE 4 Tablet Mg. 14-hydroxy-dihydro-6fi-thebainol 4-methyl ether 1.14 Lactose 74.86 Corn starch 19 Talc 4 Magnesium stearate 1 The above ingredients were throughly mixed and compressed into a tablet (100 mg.)

10 EXAMPLE 5 Tablet Mg. 14-hydroxy-dihydro-6fl-thebainol 4-methyl ether 2 Lactose 74.72 Soluble starch 18.5 Talc 4 Magnesium stearate 0.5

In the same manner as in Example 4, a tablet was made using the above ingredients.

EXAMPLE 6 Capsule Mg. 14-hydroxy-dihydro-6 8-thebainol 4-methyl ether 1 Lactose 299 The above ingredients were thoroughly mixed and filled into a soft gelatin capsule.

The above ingredients were thoroughly mixed and granulated. The granules were then dried and screened.

What is claimed is:

1. A method for the relief of cough which comprises administering to a human subject suffering from cough at a daily dosage ranging from 3 to 12 mg. of 14-hydroxydihydro-6B-thebainol 4-methyl ether.

2. The method according to claim 1 wherein said administration is orally.

3. The method according to claim 1 wherein said administration is parenterally.

4. The method according to claim 1 wherein a daily dosage is 6 mg.

5. The method according to claim 1 wherein said thebainol is administered three times a day at a single dose of 1-4 mg.

-6. The method according to claim 1 wherein said thebainol is administered in the form of a pharmaceutical composition.

7. The method according to claim 6 wherein said pharmaceutical composition is in the form of tablets, capsules, solutions for injection or granules.

8. The method according to claim 7 wherein each tablet contains about 0.5 to 4 mg. of said thebainol.

9. The method according to claim 7 wherein each capsule contains about 0.5 to 4 mg. of said thebainol.

References Cited Chem. Abst. 59, p. 2589 h-2590 C (1963).

ALBERT T. MEYERS, Primary Examiner S. I. FRIEDMAN, Assistant Examiner 

